Demyelinating diseases are devastating maladies that affect the stability and maintenance of the insulating membrane myelin, leading to damage of the nervous tissue and threatening the standard of life of the affected individual. For a long time, the adult CNS has been considered to be depleted of cells capable of remyelinating axons. However, growing evidence shows that oligodendrocytes (OLs), the CNS myelin forming cells, have some remyelinating capacity under the appropriate circumstances. As a result, new therapeutic strategies can be envisioned to repair demyelination. OLs are plastic cells and several extracellular signals have been shown to play key roles in timing the development of these cells in the CNS. For example, PDGF-AA, IGF-I, Tf, NT-3 and T3 have critical and supportive effects on the proliferation, survival and differentiation of OLs in vitro and in vivo. On the other hand, OLs are susceptible to dysfunction and consequently, myelin can be damaged. Many cytokines like IL-6, TNF-a1FN-a and LT-a, which are produced in high levels in some autoimmune diseases, are particularly toxic to OLs. The effects of these molecules have been evaluated using in vitro cell cultures and explants and relatively few studies have approached the in vivo importance of these factors on glial development. In this grant, we propose to address a number of questions to study the in vivo physiological role of these factors and their relevance for therapeutic strategies. Recent studies suggest that PDGF-AA and IGF-I may be the best candidates to therapeutically treat CNS disorders where OLs are compromised. We propose to expand our studies to examine the therapeutic potential of other factors like bFGF, Tf and NT-3 and hormones like T3 and hydrocortisone in combination with PDGF-AA and IGF-I. We will test the hypothesis that remyelination can be controlled externally by providing an appropriate growth factor treatment to animals suffering from experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease Multiple Sclerosis (MS) and in animals where CNS myelin has been damaged by treatment with cuprizone. We will evaluate the benefits of modulating the critical and valuable information about the mechanisms that control oligodendrogenesis in the normal adult CNS and in pathological conditions and will be essential for future design or effective therapies to attempt the remyelination of adult CNS.